(a) Field of the Invention
The invention relates generally to the preparation and use of an injectable self-setting mineral-polymer composition for repairing, replacing or therapeutically treating tissues and body parts. More particularly, the present invention includes the injectable self-setting mineral-polymer composition.
(b) Description of Prior Art
A large quantity of biomaterials has been introduced for hard-tissue repair and formation, including natural or synthetic materials, pure organic or inorganic materials, and organo-inorganic biohybrid or hybrid materials.
Conductive hard-tissue implants are passive biomaterials that provide a matrix to favor and support a new hard-tissue ingrowth and repair. They generally do not provide any osteogenesis property, in the meaning that such materials do not supply, by themselves, any osteogenesis or hard-tissue inductive factors, or any hard-tissue healing accelerators. Conductive structures have typically to favor the own ingrowth and reorganization of hard-tissues (Ex: osteoconductive materials).
The main constituent of hard-tissues is biological apatite that is commonly found in bone and teeth (65-98%). Calcium and phosphate ions are commonly contained in body fluids and mineral contents of hard tissues, including bones, dentine and dental enamel. They may also additionally contain other constituents such as carbonates, magnesium or sodium. Hydroxyapatite is generally recognized as being a calcium phosphate material with a crystal structure very close to biological apatite. Calcium phosphates, and some other ceramics, were found to be very useful biocompatible materials for hard-tissue repair. Today, a large family of ceramic biomaterials having different forms is available for repairing hard-tissues, and includes calcium phosphates, calcium carbonates, bioglasses and pure natural minerals.
Bone Repair and Formation
Conductive matrices for hard-tissue repair are designed to provide adequate compositions and architectures that favor the ingrowth of hard-tissue by its own. They are inserted into a defect, thus contacting mature hard-tissue cells that are capable of invading the repairing matrix and forming mineral networks to complete tissue ingrowth. Typical examples are generally related to osteoconductive materials for bone tissues.
Conductive hard-tissue implants have received a considerable attention, particularly in bone surgery. Grafting materials for defect filling and bone repair include autografts, xenografts, demineralized bone matrix, porous ceramics such as calcium phosphates, calcium carbonates, coral, nacre, bioglasses, organic matrices (polymers, collagen and other biological macromolecules) as well as organo-inorganic biohybrid or hybrid materials such as organo-apatites.
Implants for filling and repairing defects are currently solids, sometimes gels and hydrogels that enable the ingrowth and conduction of the hard-tissue. Porous or plain solids may be used. Plain solid implants stimulate hard-tissue ingrowth through their own resorption. Porosity may be inherent to the material architecture (true porosity), or be interstitial. Calcium phosphates have been the preferred bone biomaterials. In a large number of animal and human studies, they have been shown to be biocompatible, and bone growth promoters. Targeted calcium phosphate ceramics are tricalcium phosphates, amorphous calcium phosphate, octacalcium phosphate, and apatitic compounds. Hydroxyapatite [Ca10(PO4)6(OH)2], calcium-deficient apatite, fluorinated apatite [Ca10(PO4)6F2], and carbonated apatite [Ca10-xHax(PO4)6-x(CO3)x(OH)2] are the most representative apatitic compounds. Synthetic or sintered apatites may be prepared.
Most calcium phosphate ceramics are prepared as granules or block materials. Block materials can be prepared in various geometries such as rods, cylinders, rectangular shapes, etc. However, ceramic blocks must be re-shaped before implantation to fit exactly the defect size and geometry, which makes heavier and longer the handling and clinical application. Furthermore, calcium phosphate blocks are very brittle and difficult to shape, and consequently the interface between the bone tissue and ceramic implant is not perfectly continuous which may impair the osteoconduction efficiency. Calcium phosphate granules are currently produced with a wide size distribution, and available from 10 microns to 2.5 mm, but preferably used with a size between 90 and 400 microns. Granules can be injected, or at least administered through less invasive techniques, so as to fulfill the tissue defect. But granules have a mobility problem in situ, which limits their use and efficiency.
Ceramics such as calcium carbonates, coral or nacre are equally proposed under granular or block form, and present similar problems. Bioglasses are generally under granular or microspheric form (Bioglass®, USBiomaterials; Biogran®, Orthovita; Perioglass®).
Collagen, a component of soft- and hard-tissues, and Bone Demineralized Matrix (BDM) are the current organic materials for filling hard-tissue defects. Collagen was associated with mineral to form composite materials such as Collapat® or Collagraft® (NeuColl), Cerapatite-Collagen® (Ceraver-Osteal), Ossatite® composite (MCP). Polymeric materials such as polylactic acid, polyglycolic acid, polylactic-co-glycolic acid microspheres, etc were also proposed for bone defect filling and repair, but are less current than calcium phosphate granular materials. One new development is Immix® (Osteobiologics) bone-grafting material based on PLA/GA.
Injectable Bone Substitutes
Inorganic or organo-inorganic bone cements and/or remineralizing systems form another family of promising injectable self-setting or self-hardening osteoarticular materials. Self-setting cements were typically composed of a solid mineral component mixed with a liquid component. Solid mineral components generally contain calcium phosphates, such as monocalcium phosphates [Ca(H2PO4)2.H20], dicalcium phosphates [CaHPO4, CaHPO4.2H2O], tricalcium phosphates [α-Ca3(PO4)2, β-Ca3(PO4)2] and tetracalcium phosphates [Ca4(PO4)O], with or without other calcium sources and/or phosphate sources, calcium carbonates and/or organic or inorganic additives.
Calcium phosphate remineralizing and cement systems differ by the liquid to solid ratio. Cements are produced from calcium phosphate powder that was finely ground, typically around 5 microns. Calcium phosphate solid component was also mixed with much less liquid, thus forming a paste rather than a slurry. Remineralization was generally promoted by using particles of greater size since they slow the remineralization rate and prolong the remineralization potential.
Porosity of the resulting self-setting calcium phosphate materials may benefit to the hard-tissue repair. It is reached by adding a highly soluble porogen ingredient to the calcium phosphate composition. The composition, including the water-soluble inclusions, is subjected to pressure to form compact materials. Hot water may be used to dissolve the porogenic compound. Others suggested that cement porosity is controlled by the size of dry ingredients. Large-size calcium phosphate granules (0.7-1.0 mm) in the cement composition were found to provide larger pores than small-size granules (0.1-0.3 mm).
Self-setting calcium phosphate composition is transformed following the reaction in situ of calcium phosphate ingredients which is a dissolution/reprecipitation process. The reactivity in situ of calcium phosphates is controlled by chemical and physical conditions. Chemical purity of calcium phosphates may greatly alter the reactivity. Tetracalcium phosphate (TTCP) purity was showed to influence setting and performances of calcium phosphate cements, for example the cement setting time and mechanical strength. TTCP is highly reactive to water, such as air moisture, thus forming calcium oxide or hydroxide, and hydroxyapatite at the TTCP granule surface. Formulation pH and temperature influence the reactivity of calcium phosphates. The size of calcium phosphate particles was also reported to significantly control the reactivity, thus possibly slowing the reaction and retarding the hardening or setting rate when too large. Granule size is related to the exposed surface area, and possibly influences the initial composition of the ingredients, the final dry product composition, and hence the mixing, mechanical and physical properties.
Single calcium phosphate cements cannot set in hard-consistency materials. They were also reported not to be able to maintain a constant pH, and to lack of mineralizing capacity. Driskell et al. (U.S. Pat. No. 3,913,229) described a mixture of tricalcium phosphates and dicalcium phosphate that does not self-harden, and has insufficient remineralizing capacity.
Brown and Chow (U.S. Pat. Nos. 4,612,053; 4,518,430; and Re33,221) proposed a self-setting composition based upon an aqueous mixture of tetracalcium phosphate (TTCP) with at least another calcium phosphate component in excess, selected from dicalcium phosphate or brushite, tricalcium phosphates and modified tricalcium phosphates, octacalcium phosphate [Ca8H2(PO4)6.5H20] which was able to self-harden into a cement at an ambient temperature. Additional calcium or phosphate sources consisted mainly in CaCl2, Ca(C2H3O2), NaH2PO4 and NH4H2PO4. The slurry containing calcium phosphates in excess had a pH in the vicinity of 7.4. This cement paste was proposed first for dental restorative applications although many orthopedic indications were proposed. Later, Chow and Takagi (U.S. Pat. No. 5,545,254) showed that the preparation of TTCP free of surface calcium oxide or hydroxyapatite greatly improved the quality of such bone cements for dental and orthopedic applications. Remineralization and cement compositions were biocompatible precursors of hydroxyapatite, having two properties: a) they were self-hardening and form materials with sufficient strengths for medical and dental applications; b) they were resorbed in situ and progressively replaced by new hard-tissues.
Liu and Chung (U.S. Pat. No. 5,149,368) proposed other TTCP-based cement formulations where TTCP was admixed with water and acidic citrate to form a paste having a pH greater than 5. The weight ratio of powder to liquid was between 2:1 and 15:1. Constantz et al. (U.S. Pat. No. 5,053,212) developed a composition precursor of hydroxyapatite by admixing a calcium source with an acidic phosphate source. In the preferred embodiment, TTCP was mixed with calcium oxides, calcium carbonates (typically CaCO3), monocalcium phosphate monohydrate (MCPM) and/or orthophosphoric acid. Calcium to phosphate ration was about 1.25-2.0 to 1.0. Later, another bone cement was described where a dry component was admixed with a compatible lubricant and an anti-microbial agent (U.S. Pat. No. 5,968,253). Its dry component was made of reactive α-tricalcium phosphate (60-95% dry wt.), monocalcium phosphate monohydrate (1-20% dry wt.) and calcium carbonate (5-25% dry wt.), and admixed to a phosphate buffer having a pH between 4.0 and 11.0. The anti-microbial agent such as gentamycin or vancomycin was added to the liquid component at 0.001 to 3.0% wt. This flowable composition was the basis of the Norian SRS® bone cement. This composition involved conversion of MCPM into dicalcium phosphate, then formation of hydroxyapatite by reaction of dicalcium phosphate with TTCP. It was setting in approximately 15 minutes, and reached a compression strength about 40 MPa. Another proposed cement composition gave a 2-10% wt. carbonated apatite (U.S. Pat. No. 5,900,254). Dry composition includes a partially neutralized phosphoric acid such as the MCPM and a calcium phosphate source such as the TCP. Calcium carbonate (9-70% dry wt.) was added to the dry component. The liquid component was a 0.01 to 2.0M phosphate buffer, either a sodium phosphate or sodium carbonate, with a pH between 6.0 and 11.0. This composition had the properties of a) having a calcium to phosphate molar ratio of 1.33 to 2.0; b) being not sintered or hydrothermally prepared; and c) having a compression strength above 5500 psi.
Granular bone cements were proposed by admixing a monocalcium phosphate and/or dicalcium phosphates to a α-tricalcium phosphate or a tetracalcium phosphate (U.S. Pat. No. 5,338,356). Calcium to Phosphate ratio was between 1.39 and 1.45, and calcium phosphate granules were 0.1 to 1.0 mm in size. Liquid to Solid ratio varied from 0.3 to 30. Hirano and Hanno (U.S. Pat. No. 5,152,836) also proposed a hydraulic cement made of a mixture of tricalcium phosphates and dicalcium phosphates with a calcium to phosphate ratio between 1.4 and 1.5. Water was used as the hardening liquid component, and water containing soluble sodium was preferred for short hardening times and enhanced cement strengths.
A calcium phosphate cement was proposed and prepared from a TCP/TTCP dry mixture in a liquid component containing calcium and phosphate sources. Liquid component typically contained phosphoric acid, and calcium hydroxide or calcium carbonate. Additives were optionally added to the cement composition, preferably lactic acid (<4% wt.), alginate or gum (<2% wt.), and/or magnesium or potassium glycerophosphate (<15% wt.). Calcium to phosphate ratio of the dry component was about 1.70 to 1.85 while the one of the liquid component was between 0.2 and 0.5. This cement gave a crystalline hydroxyapatite biomaterial with a compressive strength about 15 to 25 MPa.
A calcium orthophosphate composition that hardens in 100% humidity environments into a calcium phosphate cement was composed of a mixture of three to four calcium sources with water. The composition had a pH ranging between 6.5 and 8.0. Calcium sources were selected preferably among monocalcium phosphate monohydrate (MCPM), dicalcium phosphate or brushite, tricalcium phosphates, and modified tricalcium phosphates, octacalcium phosphate, apatites, and other calcium compounds such as Ca8.5Na1.5(PO4)4.5(CO3)2.5, Ca9(PO4)4.5(CO3)1.5, Ca4Mg5(PO4)6, CaZn2(PO4)2, CaKPO4, CaNaPO4, Ca10Na(PO4)7, Ca2PO4Cl, CaO, Ca(OH)2, CaMgO2 and Ca10(PO4)6Cl2.
Basic calcium phosphate cements self-setting in hydroxyapatite were developed by Chow and Takagi (U.S. Pat. Nos. 5,525,148 and 5,954,867). Liquid components contained liquid phosphate component having a pH above 12.5 (phosphate >0.2 mol/l). Solid calcium phosphate component had a Calcium to Phosphate between 3.0 and 5.0, included various calcium phosphates, except TTCP, and a calcium source. Proposed calcium phosphates were dicalcium phosphates, tricalcium phosphates, octacalcium phosphate and/or amorphous calcium phosphate. Additional sources of calcium were selected typically among calcium carbonates, calcium oxides, and calcium hydroxides. Additional minerals were also added in minor concentrations. The pH of the composition was potentially adjusted above 12.5 by adding sodium hydroxide.
Commercial developments in calcium phosphate bone cements are given by SRS® (Norian), BoneSource® (Stryker/Howmedica), alpha-BSM® (ETEX Corp.), all three giving carbonated apatite in situ, and Cementek® (Teknimed SA).
Most common calcium phosphates in self-setting cements were selected from monocalcium phosphate monohydrate [Ca(H2PO4)2.H20], dicalcium phosphate (DCP) or brushite [CaHPO4, CaHPO4.2H2O], tricalcium phosphate (TCP) [α-Ca3(PO4)2, β-Ca3(PO4)2], tetracalcium phosphate (TTCP)[Ca4(PO4)O], amorphous calcium phosphate (ACP)[Ca3(PO4)2.H2O], octacalcium phosphate (OCP) [Ca8H2(PO4)6. 5H20], and apatites [Ca10(PO4)6(OH)2].
All calcium phosphates have different dissolution rate at a given pH. For a calcium to phosphate molar ratio above 1.5, the dissolution rate can be defined (at least up to a pH about 10) as follows: Tetracalcium phosphate>α-tricalcium phosphate>β-tricalcium phosphate>hydroxyapatite.
Calcium phosphates have also a relative acidic or basic character, thus increasing acidity or basicity.
Acidic components generally include, in an acidity order: monocalcium phosphate monohydrate>dicalcium phosphate>octacalcium phosphate>amorphous calcium phosphate=β-tricalcium phosphate=α-tricalcium phosphate=calcium-deficient apatite. Monocalcium phosphate monohydrate is generally used as acidic calcium phosphate source when necessary.
Basic calcium phosphates generally include, in a basicity order: tetracalcium phosphate>precipitated hydroxyapatite=sintered hydroxyapatite>α-tricalcium phosphate=calcium-deficient apatite=β-tricalcium phosphate=amorphous calcium phosphate. Calcium sources such as calcium oxides and hydroxides are more basic than tetracalcium phosphate.
Exothermic setting reactions may be damageable to living tissues and cells in situ. High temperatures generated by the cement setting being undesirable, it is thus desirable to keep the setting temperature well below 50-60° C. Exothermic effects in calcium phosphate cements are typically obtained by reacting calcium oxides with acidic phosphate sources. The transformation of calcium oxide into calcium hydroxide is recognized to be exothermic. Pressure level of cement composition may also change during the setting reaction. Calcium carbonate [CaCO3] is for neutralizing and buffering the formulation, but generates carbon dioxide gas. In situ formation of carbon dioxide gas is susceptible of pressure elevation, and may induce unexpected structural modifications or changes of the resulting material. Calcium carbonate, and other carbonates, in cement composition must be specially considered for this gas supply and pressure increase in situ.
Incorporation of polymer in cement composition was proposed to give some specific properties: a) to improve the handling properties and wettability of the cement; b) to avoid the cement composition to disintegrate in aqueous media such as the physiological fluids, and allow to pre-shape the composition; as a consequence, this reduced the need for removal of body fluid, hemostasis, or the like.
Polyacid or polyol polymers, polysaccharides and polypetidics were preferentially chosen for incorporation in calcium phosphate cement compositions. Polycarboxylics (polycarboxylic acid), poly(ethylene glycol), poly(propylene glycol), methyl cellulose, poly(vinyl alcohol), carboxymethyl cellulose, hydroxypropyl methylcellulose, and the like, were proposed as polymeric components. Collagen was optionally introduced in a cement composition by Constantz et al. (U.S. Pat. No. 5,053,212). Chitin, chitosan, starch, gum, pectic acid, alginic acid, hyaluronic acid, chondroitin sulfuric acid, dextran sulfuric acid and their salts were reported as potent polysaccharide ingredient (U.S. Pat. Nos. 5,152,836; and 5,980,625; and European patent application publication No. EP-899,247 A1).
Chitosan was admixed in many liquid components of calcium phosphate cement compositions. Chitosan in citric, malic, or phosphoric acid aqueous medium was the liquid component of a self-setting TCP or TCP/TTCP cement (U.S. Pat. Nos. 5,281,404 and 5,180,426). Chitosan in bone cements or substitutes was also studied in the scientific literature, as reported by Leroux et al. (Bone, Vol. 25, No 2, supplement, 1999:31S-34S), Hidaka et al. (J. Biomed. Mat. Res., 46:418-423, 1999), Ito (Biomaterials, 12:41-45, 1991). It has also been reported the use of chitosan in calcium phosphate compositions. Typically, chitosan 0.05% wt. in an acidic aqueous medium (acid 25-55% wt.) was used as lubricant for a solid component consisting in a mixture of TCP and TTCP. Chitosan was chosen to prevent the powder dispersion and cement disintegration.
Osteoconduction and osteogenic performances of chitosan based materials were reviewed, and applied to biomaterials development. Chitosan with immobilized polysaccharides such as heparin, heparan sulfate, chondroitin sulfate and dextran sulfate was reported for stimulating hard-tissue regeneration by Hansson et al. (International Patent Application publication WO96/02259). Osteoinductive compositions were also developed by admixing hydroxyapatite and bone-derived osteoinductive gelatin to chitosan solutions (U.S. Pat. No. 5,618,339).
It would be highly desirable to be provided with a self-hardening mineral polymer hybrid composition with attractive performance for biomedical uses.
It would also be highly desirable to be provided with a gel-forming liquid component that enables to enhance the handling and cohesion properties of a new self-hardening material.
It would still be highly desirable to be provided with a liquid component that contains a chitosan solution, free of insoluble particle, with a pH close to 7.0 and a thermo-gelling character. This would be innovative and allow developing an in-situ self-hardening material based upon a mineral composition.